Based on excess over requirement, methionine is the most toxic amino acid. Necrosis of the liver, kidney, pancreas, spleen and increased fragility of red blood cells are evident in young animals consuming excess methionine whereas consumption of similar levels are not damaging in the adult. Work from our laboratory indicates that metabolism of methionine independent of S-adenosylmethionine formation is related to the toxicity of methionine. We have shown that metabolism of methionine by this pathway(s) yields 3-methylthiopropionate, which yields methanthiol and hydrogen sulfide two extremely toxic compounds. Consumption of high levels of methylthiopropionate results in grossly abnormal red cells and an enlarged spleen with a marked accumulation of hemosiderin. Our thesis is that the methanthiol and hydrogen sulfide produced, form mixed disulfides in membranes thus effecting essential structural disulfides an weaken the membrane. We further postulate that enzymes with SH active centers may be inhibited by mixed disulfide formation. These insults ultimately lead to the death of the cell. The work proposed is designed to estimate the magnitude of methionine metabolism by S-adenosylmethionine dependent and independent pathways by estimating the rate of turnover of the methionine and S-adenosylmethionine methyl carbons. Experiments with pig and monkey livers are expected to show another pathway of methionine metabolism independent of S-adenosylmethionine formation which yield methanthiol. The effect of adaptaton to a high methionine diet and the effect of age will be incorporated into studies on 3-methylthiopropionate metabolism. The relationship between red blood cell morphological changes and binding of methanthiol to red blood cell ghosts and contents will be investigated. An analytical system to estimate the concentration of 3-methylthiopropionate in relation to methionine metabolism will be further developed and applied to in vitro incubations and intact animals. These studies provide metabolic insight into inherited disorders of methionine metabolism namely hypermethioninemia and homocystinuria.